The invention disclosed herein concerns a process for making propargylic alcohols by zinc-mediated catalytic, asymmetric addition of acetylenes to aldehydes. Enantioselective addition of organometallic reagents to aldehydes affords optically active secondary alcohols. Such optically active secondary alcohols serve as intermediates in many naturally occurring compounds, biologically active compounds, and materials such as liquid crystals. The resultant alcohols are also important as synthetic intermediates of various fuctionalities which include halide, amine ester and ether.
Various publications of related zinc mediated and zinc acetylide procedures have been cited in the literature. See Noyori, R., et al., Angewandte Chemie Int. Ed., 30 ,49-68, (1991); Soai, K., et al., Chemical Review, 92, 833-856, (1992); Seiji, N. et al., J. of Chemical Society Perkin Trans., 1, 937-943, (1990); Ramos Tombo, G. S., et al., Synlett, 547, (1990); Thompson, A., et al, Tetrahedron Letters, 36, 8937-8940, (1995); Huffman, M., et al, J. of Organic Chemistry, 60 (6), 1590-1594 (1995); Miyuki, I. et al., Tetrahedron Assymetry, 5, No. 10, 1901-1904 (1994); and Corey, E. J., et al., J. of American Chemical Society, 116, 3151-3152, (1994).
In the past, asymmetric acetylide additions to carbonyl compounds were performed in either of two ways, stoichiometrically or catalytically. In the stoichiometric case, a large amount of the chiral ligand is required. Even with high enantiomeric excess (ee), this is undesirable from the point of view of cost and additional equipment needed to recover the ligand. In addition, many methods use the intermediacy of a strong base to generate an acetylide species, leading to limits on the functionality present in the substrates.
In the catalytic cases reported, the enantiomeric excesses obtained have been low. In addition, the reported procedures use a two-fold excess of a difficult to prepare diacetylenic zinc species. In effect, three acetylene groups are discarded. Although this particular catalytic methods produces high % ee, this method is limited in that a preformed dialkylzinc species must be used.
The disadvantages of the processes employed in the prior art are the use of a stoichiometric quantity of a chiral ligand or in the catalytic mode, the preformation of a diacetylenic zinc species.
The advantages of the process employed in the present invention include:
(1) no preformation of zinc reagents, the free acetylene is used in the reaction. PA1 (2) a catalytic quantity, typically 10 mole %, of the chiral ligand is used. PA1 (3) ee's are moderate to high.
The invention disclosed herein provides a process for the catalytic asymmetric addition of substituted acetylenes to aldehydes, furnishing propargylic alcohols in moderate to high ee.